GSK-3 was found to be a kinase that phosphorylates and deactivates glycogen synthase. It has been clarified at present that it is involved in the oxidation and synthesis of fatty acid, or abnormality in insulin signaling pathway via phosphates of various protein groups related to metabolism and signal is transduction such as AcylCoA carboxylase, ATP-citrate lyase, Insulin receptor substrate-1 and the like. Moreover, GSK-3 is known to phosphorylate various structural proteins and regulate functions thereof. Particularly, phosphorylation of tau protein has been attracting attention in relation to the onset of Alzheimer's disease. In addition, GSK-3 is involved in phosphorylation of various transcription factors, and particularly, activates activator protein-1, cyclic AMP response element binding protein, nuclear factor of activated T cells, heat shock factor-1, β-catenin, Myc, C/EBP, NFκ-b or the like. Therefore, its inhibitor is expected to be a therapeutic drug for Alzheimer's disease, cerebral stroke, bipolar disorder, schizophrenia, cancer, bone disease, type II diabetes and obesity.
In insulin signaling pathway, GSK-3 is negatively regulated by phosphorylation via Akt (protein kinase B: also described as PKB). In diabetic patients, increased activity of GSK-3 and synthesis of fatty acids and/or insulin resistance are considered to be synergistically induced by the overlapped occurrence of promoted GSK-3 gene expression and insulin dysfunction. Since GSK-3 positively regulates the process of adipocyte differentiation and/or maturation via phosphorylation of C/EBP, increased GSK-3 activity triggers obesity, which in turn aggravates diabetes. In fact, it has been reported that administration of GSK-3 inhibitor improves insulin resistance of model animals of Type II diabetes. We have elucidated as our own findings that GSK-3 inhibitor suppresses adipocyte differentiation and/or maturation, expresses an antiobesity effect, and promotes sugar-dependent insulin secretory action of pancreatic β cells. Given these findings in combination, GSK-3 is considered to be additively and/or synergistically involved in the onset of diabetes in the insulin targeting tissues such as liver, skeletal muscle, fat, pancreas and the like, and GSK-3 inhibitor can be an effective therapeutic drug for obesity and/or diabetes because it eliminates these factors.
Activation of GSK-3 in Alzheimer's brain has been reported, and therefore, GSK-3 is considered to be involved in senile plaque and neurofibrillary tangle, which are the two major pathological findings in Alzheimer's disease. In the metabolism of amyloid precursor proteins, GSK-3 is linked to γ secretase to positively regulate the production of β amyloid protein, a main constituent component of senile plaque. As for tau protein, which is a main constituent component of neurofibrillary tangle, GSK-3 is considered to facilitate phosphorylation of the protein, prevent axonal transport, and finally induce neurodegeneration. It is also known that GSK-3 is located downstream of the PI3 kinase-Akt system signal transduction important for the neuronal cell survival, and activated during neuronal cell death. Accordingly, GSK-3 inhibitor is expected to not only suppress neurodegeneration but also suppress two major pathological findings of Alzheimer's disease. As our own findings, we have clarified that PI3 kinase-Akt system signal transduction plays a key role in neurogenesis and neuroregeneration and found that inhibition of GSK-3 located downstream thereof can facilitate neurogenesis. Considering our new findings in combination, there is a possibility that GSK-3 inhibitor suppresses two major pathological findings of Alzheimer's disease and additionally suppresses neurodegeneration, induces neurogenesis and achieves regeneration of function. It is assumed that GSK-3 inhibitor having the above-mentioned properties can be an ultimate therapeutic drug for Alzheimer's disease, and can also be effective as a therapeutic drug for neurodegenerative diseases such as Parkinson's disease and the like, cerebrovascular disorders and the like. Since a report has recently documented that Akt system signal transduction decreases in schizophrenia, GSK-3 inhibitor may become a completely new type of therapeutic drug for schizophrenia.
The following are known as regards the relationship between GSK-3 and diseases such as neurological disorder, diabetes, cancer, inflammatory disease (sepsis shock etc.), osteoporosis, alopecia and the like.
In neurological disorder, GSK-3 relates to neuronal cell death and nerve cell survival, and induces apoptosis by overexpression of GSK-3 (non-patent document 1). In addition, GSK-3 phosphorylates tau protein which causes neurofibrillary tangle (non-patent document 2).
In diabetes, GSK-3 phosphorylates glycogen synthase to decrease the activity, and inhibits glucose uptake in skeletal muscle to decrease the insulin reactivity (non-patent documents 3 and 4).
In cancer, a GSK-3 inhibitor induced apoptosis in a certain kind of cancer cells (non-patent document 5).
In inflammatory disease (sepsis shock etc.), GSK-3 acts on Toll-like receptor signal, and controls the production of inflammatory and anti-inflammatory cytokines. Since inhibition of GSK-3 suppresses production of inflammatory cytokine and increases production of anti-inflammatory cytokine, a GSK-3 inhibitor is useful for inflammatory diseases (non-patent document 6).
In osteoporosis and alopecia, GSK-3 stabilizes β-catenin via Wnt signal, and is involved in bone mass increase and hair development (non-patent documents 7 and 8).
As a compound having a GSK-3β inhibitory activity, a compound represented by the formula:
wherein R0 is hydrogen, alkyl and the like; R1 is hydrogen; R2 is hydrogen, alkyl and the like; R3 is (1) alkyl or haloalkyl, (2) cycloalkyl optionally having substituents and the like; R4 is alkoxycarbonyl, alkylcarbonyl and the like; and R5 is alkyl, phenylaminoalkyl etc. is known (patent document 1).
Non-patent document 9 describes a compound represented by the following formula:
wherein (1) n=1, Z=H; (2) n=2, Z=H; (3) n=1, Z=3-Cl; (4) n=1, Z=2-Cl; (5) n=1, Z=3-I; (6) n=1, Z=4-I; (7) n=1, Z=3-F; (8) n=1, Z=3-COOH; (9) n=1, Z=3-COOCH3; (10) n=1, Z=3-(5-methyl-1,3,4-oxadiazol-2-yl); (11) n=1, Z=4-COOH; (12) n=1, Z=4-CH2COOH; (13) n=1, Z=4-(2-fluorobenzylcarbamoylmethyl), which has a GSK-3β inhibitory activity.
In addition, patent document 2 describes a compound represented by the following formula:
wherein X is N or CH; Y is a group: W(CH2), (CH2)W and the like; R1 is a phenyl group or a heterocyclic group containing 1 to 4 hetero atoms selected from N, O and S(O)m, which is optionally substituted by one or more R3; each R3 is selected from the group comprising amino, hydrogen and the like; R2 is selected from the group comprising hydrogen, halogen and the like; U is phenyl or 5- to 10-membered monocyclic or bicyclic system wherein one or more carbon atoms are optionally substituted by a hetero atom selected from N, O and S(O)m, which is substituted by at least one R6 and optionally substituted by at least one R4.
On the other hand, as an oxadiazole compound, the following compound is known.    (1) As a melanin-concentrating hormone antagonist, a compound represented by the formula:
wherein Ar1 is a cyclic group optionally substituted by 1 to 5 groups selected from a C1-C8 alkyl group etc.; L1 is a bond or a divalent linker represented by the formula: X2—(CR3R4)m-X3; Ar2 is a 5-membered monocyclic aromatic heterocyclic group or its positional isomer, which is optionally substituted by 1 to 3 substituents selected from a C1-C8 alkyl group etc.; Ar3 is an optionally substituted bicyclic aromatic or nonaromatic group; L2 is a divalent linker represented by the formula: X4—(CR3R4)m—X3; and R1 and R2 are each independently hydrogen, C1-C8 alkyl etc., which is useful for the treatment of type 2 diabetes, diabetes-associated disease or obesity, is reported (patent document 3).    (2) A compound represented by the formula:
wherein A is a bond, —(CR2)a— and the like; R1 is aryl, heteroaryl and the like; and R2 is —R3, —R4, —(CH2)bC(═O)R5 etc., which is used for the treatment or prophylaxis of protein kinase associated disease, for example, inflammatory disease, diabetes, obesity and the like, is reported (patent document 4).    (3) As a JNK inhibitor, a compound represented by the formula:
wherein A is a bond, —(CH2)a— and the like; R1 is aryl, heteroaryl and the like; and R2 is —R3, —R4, —(CH2)bC(═O)R5 etc., is reported (patent document 5).    (4) As a compound having a JNK inhibitory activity, a compound represented by the formula:
wherein R1 is a group represented by the formula: —(CO)h—(NRa)j—(CRb═CRc)k—Ar; Cy is a 5- or 6-membered aromatic heterocyclic group; V is a group represented by the formula: -L-X—Y; and n is 0, 1, 2, 3 or 4, is reported (patent document 6).    (5) A compound represented by the formula:
and the like, which is used for the treatment of a central neurological disease, is reported (patent document 7).    (6) As a JNK inhibitor, a compound represented by the formula:
wherein A is a bond, —(CR2)a— and the like; R1 is aryl, heteroaryl and the like; and R2 is —R3, —R4, —(CR2)bC(═O)R5 etc., is reported (patent document 8).    (7) A compound represented by the formula:
wherein n is 1, 2 or 3; X is O, S or Se; Ar is an aromatic cyclic hydrocarbon (aryl) group or an aromatic heterocyclic (heteroaryl) group, which is useful for the treatment of central neurological diseases, is reported (patent document 9).    (8) The following compounds
having a 1H-benzimidazol-6-yl group are known.    (9) The following compounds
having a 1H-benzotriazol-6-yl group are known.    (10) Non-patent documents 10 and 11 describe the following compound (2,5-bis(3-phenyl-2,1-benzisoxazol-5-yl)-1,3,4-oxadiazole)
    (11) Patent document 10 describes the following compounds (N-ethyl-N′-[6-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-2-yl]urea and N-ethyl-N′-[6-(1,3,4-oxadiazol-2-yl)-1H-benzimidazol-2-yl]urea):
    (12) Non-patent documents 12, 13 and 14 describe the following compound (2,5-bis(benzo[1,3]dioxol-5-yl)-1,3,4-oxadiazole):
    (13) Patent document 11 describes the following compound (N,N′-diethyl-N″-{5-[5-(quinoxalin-6-yl)-1,3,4-oxadiazol-2-ylsulfanylmethyl]pyrimidin-4-yl}guanidine):
    (14) Non-patent document 15 describes the following compounds (phenyl-[5-(6-quinolyl)-1,3,4-oxadiazol-2-yl]amine, cyclohexyl-[5-(6-quinolyl)-1,3,4-oxadiazol-2-yl]amine, ethyl-[5-(6-quinolyl)-1,3,4-oxadiazol-2-yl]amine, and [5-(6-quinolyl)-1,3,4-oxadiazol-2-yl]-4-tolylamine):

However, it has not been known heretofore that these oxadiazole compounds have a GSK-3 inhibitory action.    patent document 1: WO04/014910    patent document 2: U.S. Pat. No. 6,391,874    patent document 3: WO05/040157    patent document 4: US-A-2005/0009876    patent document 5: US-A-2004/0127536    patent document 6: WO03/101968    patent document 7: WO02/050062    patent document 8: WO02/010137    patent document 9: WO04/029053    patent document 10: WO02/060879    patent document 11: WO00/004014    non-patent document 1: J. Biol. Chem. 273, 19929-19932 (1998)    non-patent document 2: Acta Neuropathology, 103, 91 (2002)    non-patent document 3: Diabetes 49, 263-271 (2000)    non-patent document 4: Diabetes 50, 937-946 (2001)    non-patent document 5: Mol. Cancer Ther. 2, 1215-1222 (2003)    non-patent document 6: Nature Immunology, 6, 777-784 (2005)    non-patent document 7: Journal of Bone Mineral Research, 21, 910-920 (2006)    non-patent document 8: Cell, 95, 605 (1998)    non-patent document 9: Bioorg. Med. Chem. Lett. (2002), 12, 1525-1528    non-patent document 10: Materialy Mezhdunarodnoi Konferentsii, “Khimiya i Biologicheskaya Aktivnost Azotistykh Geterotsiklov i Alkaloidov”, Oct. 9-12, 2001 (2001), Volume 1, 452-457    non-patent document 11: Izvestiya Vysshikh Uchebnykh Zavedenii, Khimiya i Khimicheskaya Tekhnologiya (1998), 41(6), 15-19    non-patent document 12: Tap Chi Hoa Hoc (2005), 43(3), 265-269    non-patent document 13: Farmaco, Edizione Scientifica (1984), 39(5), 414-20    non-patent document 14: Monatshefte fuer Chemie (1960), 91, 294-304    non-patent document 15: Eur. J. Med. Chem. Chim. Ther. (1996), 31(10), 819-826